Mechanisms of Ageing and Development
123 (2002) 207 213
www.elsevier.com/locate/mechagedev
Protein turnover plays a key role in aging
Alexey G. Ryazanov *, Bradley S. Nefsky
Department of Pharmacology, Uni ersity of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School,
675 Hoes Lane, Piscataway, NJ 08854, USA
Abstract
Although the molecular mechanism of aging is unknown, a progressive increase with age in the concentration of
damaged macromolecules, especially proteins, is likely to play a central role in senescent decline. In this paper, we
discuss evidence that the progressive decrease in protein synthesis and turnover can be the primary cause of the
increase in the concentration of damaged proteins with age. Conversely, protein damage itself is likely to be the cause
of the decrease in protein turnover. This could establish a positive feedback loop where the increase in protein damage
decreases the protein turnover rate, leading to a further increase in the concentration of damaged proteins. The
establishment of such a feedback loop should result in an exponential increase in the amount of protein damage a
protein damage catastrophe that could be the basis of the general deterioration observed in senescent organisms.
© 2002 Published by Elsevier Science Ireland Ltd.
Keywords: Senescent decline; Protein damage; Protein turnover; Aging; Protein oxidation; Protein damage catastrophe
molecular mechanism by which any of these genes
1. Increase in the concentration of damaged
affects life span remains unknown. Similarly, the
proteins during aging
molecular mechanism of aging in general remains
a mystery. It is also unclear whether there is a
Various genes have been identified in worms,
general, or  public , as George Martin called it,
flies and mammals whose mutation can drastically
mechanism of aging that is common to various
affect life span. For example, mutations in the
organisms, or if each type of organism ages in its
insulin signaling pathway, such as age-1 and daf-
own way (Martin et al., 1996).
2, can double life span in Caenorhabditis elegans
There is extensive evidence, however, that dam-
(Friedman and Johnson, 1988; Kenyon et al.,
age to macromolecules, especially oxidative dam-
1993), the Methuselah mutation can significantly
age, plays an important role in aging (Martin et
increase life span in Drosophila (Lin et al., 1998),
al., 1996). Increase in the concentration of dam-
and mutation of p66shc can increase life span in
aged proteins seems particularly important be-
mice (Migliaccio et al., 1999). However, the
cause it would lead to the malfunction of virtually
all biological processes. An increase in the concen-
* Corresponding author. Tel.: [phone]; fax: +1-
tration of damaged intracellular proteins as well
732-235-4073.
as an increase in the concentration of inactive or
E-mail address: [e-mail] (A.G. Ryazanov).
0047-6374/02/$ - see front matter © 2002 Published by Elsevier Science Ireland Ltd.
PII: S0047-6374(01)00337-2
208 A.G. Ryazano , B.S. Nefsky / Mechanisms of Ageing and De elopment 123 (2002) 207 213
partially active forms of various enzymes in aging proteins can result from an age-dependent de-
organisms is well-documented (reviewed in Stadt- crease in the removal of protein damage by either
man, 1988, 1992; Rothstein, 1979, 1989; Rattan, repair or replacement of the damaged protein.
1996; Gershon, 1979; Rosenberger, 1991; Gafni, The cells ability to repair protein damage, how-
1990). Extensive damage to extracellular proteins ever, seems rather limited and most forms of
such as collagen, elastin and proteoglycans is also protein damage appear to be irreversible. The
observed during aging (reviewed in Sell and Mon- only mechanism cells have to deal with irre-
nier, 1995). The age-related increase in protein versibly damaged proteins is to replace them
damage is due to various post-translational mod- through protein turnover. The decrease in protein
ifications that include oxidation of amino acid turnover with age (see below) could therefore be a
side chains, racemization of aspartyl and as- major cause of the increased concentration of
paraginyl residues, deamidation of asparaginyl damaged proteins.
and glutaminyl residues, and oxidation of
sulfhydry groups (reviewed in Stadtman, 1988,
1992). Protein misfolding is also likely to con- 2. Protein turnover in aging
tribute to the increase in the concentration of
abnormal enzymes and proteins in senescent tis- The rate of protein turnover is determined by
sues (Gafni, 1990). the combined rates of protein synthesis and degra-
Oxidation by free radicals is particularly impor- dation. Once growth is complete, organisms reach
tant in generating damaged proteins during aging a steady state in which the rate of protein synthe-
(Harman, 1956; Stadtman, 1992). There is exten- sis equals the rate of protein degradation. Most
sive evidence that the increased concentration of studies of protein metabolism in aging were fo-
oxidatively damaged proteins, can be a major cused on protein synthesis, and there is over-
contributing factor in aging (Sohal et al., 1993; whelming evidence that the rate of protein
Forster et al., 1996; Oliver et al. 1987; Carney et synthesis declines with age. This decrease in
al., 1991; Smith et al., 1991; Dubey et al., 1996; protein synthesis appears to be a universal phe-
Youngman et al., 1992). nomenon (reviewed in Makrides, 1983; Richard-
The extent of protein damage observed during son and Cheung, 1982; Van Remmen et al., 1995;
aging is quite remarkable. Roughly 20 30% of all Rattan, 1996). Since there is no pronounced de-
cellular proteins are carbonylated in aged individ- crease in protein mass with age, the age-depen-
uals (Starke-Reed and Oliver, 1989; Stadtman, dent decrease in protein synthesis must be
1992). If all other forms of oxidative damage are counterbalanced by a corresponding decrease in
included, this number probably increases to 40 protein degradation. In fact, there is experimental
50% (Stadtman, 1992). If we consider other forms evidence that certain proteolytic activities associ-
of damage, it seems likely that most protein ated with both the lysosome and proteasome de-
molecules in senescent tissues contain some form crease with age (reviewed in Van Remmen et al.,
of damage. 1995; Cuervo and Dice, 2000; Grune, 2000;
What causes the increase in the concentration Friguet et al., 2000; Keller et al., 2000). The
of damaged proteins during aging? There are two age-dependent decrease in the rate of protein
possible mechanisms: an increase in the rate at turnover is quite significant and leads to a drastic
which damage is generated or a decrease in the increase in protein half-life (see e.g. Sharma et al.,
rate at which damage is removed. Both mecha- 1979; Prasanna and Lane, 1979). As is shown in
nisms appear to be involved in aging. For exam- Fig. 1, the half-life of an average protein increases
ple, an increase in the amount of oxidatively exponentially with age in the nematode Turbatrix
damaged proteins during aging may be due to an aceti, and is increased 10-fold in old nematodes in
increase in the production of free radicals (re- comparison to young worms (Prasanna and Lane,
viewed in Sohal and Weindruch, 1996). On the 1979). The drastic decrease in protein synthesis
other hand, increased accumulation of damaged with age in C. elegans (Johnson and McCaffrey,
A.G. Ryazano , B.S. Nefsky / Mechanisms of Ageing and De elopment 123 (2002) 207 213 209
1985) suggests a similar increase in protein half-
life occurs during aging in this organism. Whole
body protein turnover is also significantly de-
creased during aging in rats (Lewis et al., 1985)
and humans (Young et al., 1975). It is striking
that despite a very significant decrease in protein
turnover during aging, there are no dramatic
changes in the spectrum of proteins synthesized in
C. elegans (Vanfleteren and DeVreese, 1994; John-
son and McCaffrey, 1985) or in the spectrum of
mRNA expressed in mammalian tissues (Goyns et
al., 1998; Lee et al., 1999). Therefore, the several-
Fig. 2. Model for the positive feedback loop between the
fold decrease in overall protein turnover implies
increase in the concentration of damaged proteins and de-
that the rate of turnover of most proteins are
creased protein turnover leading to a protein damage catastro-
decreased several-fold. phe.
As was suggested by Richardson and Cheung
(1982), an increase in protein half-life can signifi- time needed for cells to respond to external stim-
uli, and can explain diminished stress resistance
cantly decrease the rate at which protein expres-
observed with age.
sion is induced. This can significantly increase the
Decrease in protein turnover can also con-
tribute to the development of neurodegenerative
disorders that are associated with the deposition
of protein aggregates such as Parkinson s disease
and Alzheimer s disease (Alves-Rodriguez et al.,
1998; Andersen, 2000).
3. Protein damage catastrophe
Although the age-dependent decrease in protein
turnover is well-documented, the mechanism re-
sponsible for this decrease is unclear. Analysis of
the literature suggests that the activities of various
components of both the protein synthesis and
degradation machinery decline with age (reviewed
in Van Remmen et al., 1995; Cuervo and Dice,
2000; Grune, 2000; Friguet et al., 2000; Keller et
al., 2000). A possible cause of such age-dependent
decline in protein turnover can be the cumulative
effect of non-specific damage to various compo-
nents involved in protein synthesis and degrada-
tion. This could establish a positive feedback loop
where increase in protein damage decreases
Fig. 1. Exponential increase of average protein half-life with
protein synthesis and degradation rates, and this
age in the nematode Turbatrix aceti. The graph was plotted
decrease in protein turnover leads to a further
using data from Prasanna and Lane, 1979. In the inset, the ln
increase in the concentration of damaged proteins
of protein half-life is plotted against age demonstrating a
linear relationship. (Fig. 2).
210 A.G. Ryazano , B.S. Nefsky / Mechanisms of Ageing and De elopment 123 (2002) 207 213
Increase in protein damage in this model can be errors in proteins leading to an  error catastro-
described by the following equations. Let be the phe . This hypothesis was widely discussed during
rate of protein turnover and q be the concentra- the 1970s and 1980s, and several mathematical
models of  error catastrophe have been devel-
tion of damaged proteins.
oped. Although a number of studies (particularly
Then,
in tissue culture cells) found no evidence of an
 error catastrophe during aging, in the absence of
= - q
a direct test we cannot determine the extent to
dq/dt= -
which transcriptional and translational errors
contribute to senescence. Our  protein damage
Where , , and are constants. From these
catastrophe model proposes a similar feedback
two equations, the rate of the increase in the
loop in which damage to the protein synthesis and
concentration of damaged proteins can be de-
degradation machinery accelerates the accumula-
scribed as:
tion of abnormal proteins resulting in senescence.
dq/dt= - ( - q)= - + q
Unlike the  error catastrophe model, however, we
propose that protein damage (covalent modifica-
or, since - is a constant, (C):
tions and misfolding) instead of translational er-
dq/dt= q+C; rors gives rise to the abnormal proteins and that it
is the resulting decrease in protein turnover,
One can see that when q is small, dq/dt is
rather than a decrease in translational fidelity,
constant, while if q C/ , then q e t and,
that leads to the increase in the concentration of
therefore, the concentration of damaged proteins
abnormal proteins.
increases exponentially.
Although our model assumes that the decrease
Therefore, the establishment of such a feedback
of protein turnover rate with age is the result of
loop could result in an exponential increase in the
cumulative damage to the various components of
amount of protein damage, leading to a protein
the protein synthesis and degradation machinery,
damage catastrophe. An exponential increase in
it is possible that damage to some rate-limiting
the amount of damaged proteins with age was in
components is particularly important in the over-
fact observed in several studies (Oliver et al.,
all decline in protein turnover. For example, there
1987; Starke-Reed and Oliver, 1989; Stadtman,
is a consensus in the literature that the elongation
1992). A decrease in the rate of protein turnover
stage of protein synthesis is predominantly af-
with age also appears to be exponential (see Fig.
fected by aging (reviewed in Van Remmen et al.,
1), which is consistent with the idea that it is
1995). In addition, there is evidence that elonga-
caused by an exponential increase in damage to
tion factor-2 is particularly sensitive to oxidative
the components of the protein synthesis and
damage, and is one of the major carbonylated
degradation machinery. We suggest that this posi-
proteins observed during oxidative stress in rat
tive feedback loop between increasing protein
liver as well as in yeast (Cabiscol et al., 2000;
damage and decreasing protein turnover leading
Parrado et al., 1999; Ayala et al., 1996). There-
to a protein damage catastrophe may be the ma-
fore, it is possible that the overall exponential
jor cause of senescence.
decrease in protein turnover with age is due pre-
Our model is reminiscent of Orgel s error
dominantly to damage to a rate-limiting compo-
catastrophe hypothesis that suggested aging is due
nent such as an elongation factor, while damage
to an accumulation of abnormal proteins arising
to other components that are not rate-limiting do
from transcriptional and translational errors
not affect the overall decline. If this is the case,
(Orgel, 1963, 1970). He suggested that the accu- and there is a particular component whose decline
mulation of errors in the transcriptional and
in activity is responsible for the overall decrease in
translational machinery would decrease their protein turnover, then this would suggest an obvi-
fidelity, establishing a positive feedback loop, ous strategy for intervention that can increase
which would further increase the accumulation of protein turnover and extend life span.
A.G. Ryazano , B.S. Nefsky / Mechanisms of Ageing and De elopment 123 (2002) 207 213 211
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